The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers
Open accessAbstract
Importance: The association between peripheral inflammatory biomarkers and Alzheimer disease (AD) is not consistent in the literature. It is possible that chronic inflammation, rather than 1 episode of inflammation, interacts with genetic vulnerability to increase the risk for AD. Objective: To study the interaction between the apolipoprotein E (ApoE) genotype and chronic low-grade inflammation and its association with the incidence of AD. Design, Setting, and Participants: In this cohort study, data from 2656 members of the Framingham Heart Study offspring cohort (Generation 2; August 13, 1971-November 27, 2017) were evaluated, including longitudinal measures of serum C-reactive protein (CRP), diagnoses of incident dementia including AD, and brain volume. Chronic low-grade inflammation was defined as having CRP at a high cutoff level at a minimum of 2 time points. Statistical analysis was performed from December 1, 1979, to December 31, 2015. Main Outcomes and Measures: Development of AD and brain volumes. Results: Of the 3130 eligible participants, 2656 (84.9%; 1227 men and 1429 women; mean [SD] age at last CRP measurement, 61.6 [9.5] years) with both ApoE status and longitudinal CRP measurements were included in this study analysis. Median (interquartile range) CRP levels increased with mean (SD) age (43.3 [9.6] years, 0.95 mg/L [0.40-2.35 mg/L] vs 59.1 [9.6] years, 2.04 mg/L [0.93-4.75 mg/L] vs 61.6 [9.5] years, 2.21 mg/L [1.05-5.12 mg/L]; P < .001), but less so among those with ApoE4 alleles, followed by ApoE3 then ApoE2 genotypes. During the 17 years of follow-up, 194 individuals (7.3%) developed dementia, 152 (78.4%) of whom had AD. ApoE4 coupled with chronic low-grade inflammation, defined as a CRP level of 8 mg/L or higher, was associated with an increased risk of AD, especially in the absence of cardiovascular diseases (hazard ratio, 6.63; 95% CI, 1.80-24.50; P = .005), as well as an increased risk of earlier disease onset compared with ApoE4 carriers without chronic inflammation (hazard ratio, 3.52; 95% CI, 1.27-9.75; P = .009). This phenomenon was not observed among ApoE3 and ApoE2 carriers with chronic low-grade inflammation. Finally, a subset of 1761 individuals (66.3%) underwent brain magnetic resonance imaging, and the interaction between ApoE4 and chronic low-grade inflammation was associated with brain atrophy in the temporal lobe (β = -0.88, SE = 0.22; P < .001) and hippocampus (β = -0.04, SE = 0.01; P = .005), after adjusting for confounders. Conclusions and Relevance: In this study, peripheral chronic low-grade inflammation in participants with ApoE4 was associated with shortened latency for onset of AD. Rigorously treating chronic systemic inflammation based on genetic risk could be effective for the prevention and intervention of AD.
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“As some proinflammatory proteins in blood impact APOE genotypes differently for AD risk [4, 20]”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Our findings of an inflammatory phenotype in resting APOE4 iAstrocytes could explain the mechanistic link between chronic inflammation and AD pathogenesis in APOE4 carriers (Tao et al., 2018).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Tao et al., 2018
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“In APOE4 carriers, chronic inflammation has been linked to an accelerated onset of AD symptoms [77].”
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AN INVESTIGATION OF CORONARY HEART DISEASE IN FAMILIES
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Self-citationDeCarli, C., Massaro, J., Harvey, D., Hald, J., Tullberg, M., Au, R., Beiser, A., D’Agostino, R., & Wolf, P. A. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.05.004 · Cited by 680
Self-citationJEUKENDRUP, A. E., VET-JOOP, K., STURK, A., STEGEN, J. H. J. C., SENDEN, J., SARIS, W. H. M., & WAGENMAKERS, A. J. M. (2000) · Clinical Science · doi:10.1042/cs0980047 · Cited by 371
Inflammatory biomarkers are associated with total brain volume
Jefferson, A. L., Massaro, J. M., Wolf, P. A., Seshadri, S. S., Au, R., Vasan, R. S., Larson, M. G., Meigs, J. B., Keaney, J. F., Lipinska, I., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000257815.20548.df · Cited by 277
Self-citationPeriodontal disease associates with higher brain amyloid load in normal elderly
Kamer, A. R., Pirraglia, E., Tsui, W., Rusinek, H., Vallabhajosula, S., Mosconi, L., Li, Y., McHugh, P. F., Craig, R. G., Svetcov, S., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.038 · Cited by 276
Cardiac Index Is Associated With Brain Aging: The Framingham Heart Study
Jefferson, A. L., Himali, J. J., Beiser, A. S., Au, R., Massaro, J. M., Seshadri, S., Gona, P., Salton, C. J., DeCarli, C., O'Donnell, C. J., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.905091 · Cited by 256
Self-citationWilson, P. W. F., Nam, B., Pencina, M. J., D’Agostino, R. B., Benjamin, E. J., & O’Donnell, C. J. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.21.2473 · Cited by 236
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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
“Contrary to this trend in genotype, cumulative incidence of AD was shown to markedly increase as levels of serum CRP increase, with the greatest effect in APOE4 carriers [126].”
Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus
Bettcher, B. M., Tansey, M. G., Dorothée, G., & Heneka, M. T. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00549-x · Cited by 427
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 483
Webers, A., Heneka, M. T., & Gleeson, P. A. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12301 · Cited by 377
“we know about conditions associated with chronic inflammation and susceptibility to AD? There is evidence of a correlation between systemic chronic inflammation, as determined by elevated C-reactive protein, and AD risk.(100) Inflammatory conditions are also increasingly linked to AD.”
BackgroundAPOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255
Metadata
- Authors
- Tao, Q., Ang, T. F. A., DeCarli, C., Auerbach, S. H., Devine, S., Stein, T. D., Zhang, X., Massaro, J., Au, R., & Qiu, W. Q.
- Affiliations
- Boston University (US)
- University of California Davis Medical Center (US)
- Corresponding author
- Au, Rhoda
- Qiu, Wei Qiao
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2018-10-19
- Volume
- 1
- Issue
- 6
- Pages
- e183597
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC6324596
- OpenAlex
- W2896917224
- Cited by
- 239
- References
- 34
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 40 · 2023: 33 · 2022: 38 · 2021: 32 · 2020: 26 · 2019: 13
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hc25195-41-0-1)
- National Institute on Aging (P30AG010129, K24AG050842, U01AG052409, R01AG054076)
- National Heart, Lung, and Blood Institute (N01‐HC25195)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, low-grade inflammation, apolipoprotein E, APOE ε4 carriers, C-reactive protein, inflammatory markers, dementia incidence, brain volume, cardiovascular disease, Framingham Offspring cohort, APOE3, APOE2
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, C-Reactive Protein, Chronic Disease, Female, Humans, Inflammation, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors, Cohort Studies, Apolipoprotein E4
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